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Recent work has indicated significant improvement in survival in patients with advanced-stage hepatocellular carcinoma using the oral multikinase inhibitor sorafenib
Division of Gastroenterology and Hepatology
Vienna General Hospital/Medical University
Hepatocellular carcinoma (HCC) is the fifth most common tumour worldwide. Since diagnosis is often only established late in the course of the disease, in many cases the therapeutic
possibilities are limited. No more than 10% of patients will undergo curative HCC resection, and no more than a third of patients in the West, and considerably fewer in developing countries, will be able to obtain liver transplantation. The majority of patients will only obtain palliative therapy, or have no therapeutic option at all. Survival of patients in the later stages of disease is generally poor, with three-year survival of Barcelona Clinic Liver Cancer (BCLC) stage C patients estimated at 10%.
Stage-dependent prognosis of hepatocellular carcinoma
Many different prognostic models have been developed over time with the goal of estimating prognoses for patients with HCC. Currently, the BCLC staging classification is the most popular. This classification was not developed using multivariate modelling, but the stages are designed to yield the appropriate therapeutic option automatically (see Figure 1).
Curative treatment options are preferred but are suitable for only a few patients with early-stage disease. Patients with BCLC stage B still have transarterial chemoembolisation (TACE) as an option with proven efficacy. So far, patients with BCLC stage C, who have either portal macroinvasion or extrahepatic
metastasis, have had no treatment available. Survival without treatment in BCLC stage B disease is 80% and 50% at one and three years respectively, while BCLC stage C disease yields survival rates of only 30% and 10% at one and three years respectively.
Over the last 20 years much effort has been expended on developing an effective systemic treatment for HCC, albeit without much success. Neither antioestrogens such as tamoxifen, nor classical chemotherapy with doxorubicin, mitomycin C or various other agents, nor trials with growth-inhibiting hormones such as somatostatin have shown a measurable effect on patients’ survival in prospective randomised studies of advanced-stage HCC.[3,4] The reasons for this have been either poor efficacy or pronounced toxicities of chemotherapeutic drugs in patients with advanced
Considering the molecular derangements occurring in HCC, an obvious line to take was to attempt the newly developed multikinase inhibitors in hepatocellular carcinoma as well. HCC tumours are heavily vascularised, with potential susceptibility to growthinhibiting and antiangiogenic strategies.
Mechanism of action of sorafenib
Sorafenib (Nexavar®) is an orally available multikinase inhibitor. It interferes with the receptor tyrosine kinases of VEGFR1, VEGFR2, VEGFR3, PDGFRß, FLT3, RET and c-KIT. Intracellularly, sorafenib is active against RAF-kinase and inhibits the antiapoptotic protein MCL-1.
Sorafenib’s action on these different targets yields a potent antiangiogenetic action, an antiproliferative and growth inhibiting action, and a proapoptotic effect, also demonstrated in a hepatoma animal model.
Phase II data for advanced-stage HCC
In 2006 a phase II study was published that involved 137 patients with Child A and B cirrhosis. These patients with advanced-stage HCC were treated continuously with sorafenib 400mg twice a day.
In this study, 2.2% of patients had a partial response and 5.8% a minor response, and 33.6% of patients had stable disease for at least 16 weeks of therapy. Median time to progression (TTP) was 4.2 months and median overall survival was 9.2 months. Most of the patients had good liver synthetic function (72% Child A cirrhosis), and 28% of patients had intermediatestage cirrhosis (Child B). Grade 3/4 toxicities consisted of fatigue (9.5%), diarrhoea (8%) and hand–foot syndrome (5.1%). pERK expression in tumour biopsies appears to be a relevant biomarker for response to therapy. Patients with high pERK expression had a much longer TTP compared with patients with low intratumoral pERK expression. These promising data led to the design of the phase III trial of sorafenib in HCC (the SHARP trial).
Phase III data in advanced-stage HCC (SHARP)
In a large prospective double-blind multinational phase III trial of sorafenib vs placebo for treating advancedstage HCC, 602 patients with Child–Pugh A cirrhosis and no prior systemic therapy were randomised.
Sorafenib was given to 299 patients at a dose of 400mg twice a day and 303 patients received placebo. Patients in both groups were evenly distributed regarding severity of liver disease (95–98% Child–Pugh A), tumour stage (82–83% BCLC stage B tumours), vascular invasion or extrahepatic tumour spread (about 70% in each group).
Patient recruitment was terminated in April 2006 and the study was stopped prematurely in October 2006 following a recommendation by the data monitoring committee. The reason was an improvement in median survival, from 34.4 weeks in the placebo patients to 46.3 weeks in the sorafenib-treated patients, indicating a 44% improvement in overall survival.
After four months of therapy 62% of patients in the sorafenib group and 42% in the placebo group were free from progression. Time to progression, a secondary endpoint, was significantly improved, from 12.3 to 24 weeks in the
The proportion of adverse events during treatment amounted to 50% of patients, with events fairly evenly distributed between patient groups. Figures for drug-related serious adverse events were 13.9% and 9% in the sorafenib and placebo groups respectively. The most prevalent adverse events in the sorafenib group were diarrhoea, with 40%, followed by hand–foot syndrome with 21%, then anorexia and alopecia, with 14% each. Corresponding respective figures in the placebo group were 11%, 3% and 2%.
Sorafenib is the first substance with proven systemic efficacy in advanced-stage HCC and the new standard of care for patients not amenable to curative or interventional palliative therapy. Even though sorafenib has been registered by the EMEA on a very broad and unrestricted label, it should probably not be used in an unreflecting way in any patient with HCC. It is definitely the case that the drug should be used in all Child A patients not undergoing resection, liver transplantation, ethanol injection, radiofrequency ablation or chemoembolisation. Data from the phase II study as well as our own data indicate that it could be used in Child B patients as well, while Child C patients are usually too ill and in most cases will not benefit from treatment.
It is possible that patients undergoing palliative interventional treatments such as transarterial chemoembolisation could benefit from early combination treatment with sorafenib. This is currently being tested in clinical trials, and data will be available in the not too distant future. Whether combination treatment involving potentially curative interventions such as
resection, ethanol injection or radiofrequency ablation
along with sorafenib will be able to improve survival will be also tested in clinical trials. An important question will be whether combination treatment with either conventional chemotherapeutics or other targeted therapeutics will be able to improve survival in patients with advanced stage HCC.
Preliminary data on combination therapy with sorafenib and doxorubicin do not look too promising, and to date no data are available on combination with other kinase inhibitors.
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